The U.S. Government has rights in this invention pursuant to the National Institutes of Health Grant Nos. CA 44583 and CA 44704.
The present invention relates to the field of cancer diagnosis, and more specifically to the identification of new methods and cancer markers useful in the diagnosis, detection, and monitoring of human colorectal carcinoma.
Colorectal adenocarcinoma is a cancer which affects many people per year. The prognosis is poor in about 50% of the cases because the tumor is often not detected until the disease has spread and has reached a terminal stage. Early diagnosis is important to increase chances of arresting the carcinoma before it metastasizes, thereby leading to an improved prognosis.
One method of tumor diagnosis is detection of the presence of acute-phase reactant proteins, the levels of which increase in the blood in the presence of a malignant disease. Alpha-1-acid glycoprotein (AGP) is such a protein, and accordingly, has been utilized as an indicator of such malignant diseases as colorectal adenocarcinoma.
A more specific method of early tumor diagnosis is detection of the presence of a marker or antigen specific for a particular type of tumor. These normally proteinaceous markers are synthesized by the tumor, and may be found in the serum, ascites fluid, and/or on the surface of the tumor. Only a limited number of tumor markers for colorectal carcinoma have thus far been found to have clinical use. These include carcinoembryonic antigen (CEA), nonspecific cross-reacting antigen (NCA), and the sialylated Lewis A antigen (CA 19.9).
CEA in particular appears in elevated amount in patients with a variety of cancers including colorectal adenocarcinoma. It is a glycoprotein having a molecular weight of approximately 180,000 daltons. CEA contains complex oligosaccharide chains which comprise over fifty percent of the molecule by weight, and which are composed of fucose, sialic acid, N-acetyl glucosamine, galactose, and mannose. Once elicited by the tumor, circulating CEA is cleared and metabolized by the liver.
Patients whose condition has been accurately diagnosed as colorectal adenocarcinoma have demonstrated a broad range of circulating CEA levels. For example, approximately 40% of diagnosed patients have substantially no detectable CEA when initially examined. Unfortunately, there is no commercially available serodiagnostic marker which can be used to detect the tumor in these patients and to monitor therapy. On the other hand, patients with liver metastases, particularly when accompanied by underlying cholestasis, demonstrate very high CEA levels. This wide range has been attributed to many factors including (1) the rate of CEA production (which depends on tumor load, invasiveness, vascularity, differentiation, and sites of metastases), and (2) the rates of clearance and metabolism of CEA.
A recent study by the present inventors has determined that patients with high plasma CEA values may have a variant form of CEA which is cleared from the circulation by the human liver or by cultured rat Kupffer cells much more slowly than other forms of CEA. The slower rate of CEA clearance has been hypothesized to enhance the probability of CEA detection by various assays or screening procedures, therefore making it a desirable characteristic.
To determine why seemingly different forms of CEA are cleared at different rates would aid in the development of new or improved methods of carcinoma detection, identification, and monitoring. Moreover, a better understanding of the physical characteristics of the protein moiety which is recognized by the Kupffer cell CEA receptors may also lead to improved treatments for carcinomas such as colorectal adenocarcinoma. In addition, there will always exist a need to find new markers for cancers which thus far have none, such as some forms of undifferentiated or poorly differentiated colorectal adenocarcinoma and for new therapeutic methods.
Accordingly, it is an object of the present invention to identify the physical features which distinguish fast clearing CEA from slow clearing CEA.
It is another object of the present invention to provide a new cancer marker for the detection, diagnosis, and monitoring of carcinoma, and in particular, of colorectal adenocarcinoma.
Yet another object of the invention is to provide an antibody which recognizes the new cancer marker, thereby enabling the detection of carcinoma cells, and in particular, of colorectal adenocarcinoma cells.
A further object of the present invention is to provide a method of detecting and monitoring the treatment of a previously undetectable carcinoma.